Cocaine addiction is a serious public health problem with limited therapeutic options. One new idea is to incorporate aerobic exercise into early intervention treatment plans for individuals. Exercise enhances plasticity in the brain that could be used to help extinguish drug-to-context associations and cue-induced relapse, a major obstacle in addiction treatment. The long-term goal of this research program is to elucidate the mechanisms by which running weakens drug associations. The applicant has collected preliminary data showing that wheel running can facilitate extinction of conditioned place preference (CPP) for cocaine in mice if running is administered after conditioning. The applicant has also collected preliminary data demonstrating that running increases the formation of new neurons in the hippocampus, a brain region important for associative learning. The objective of this application is to (aim 1) determine the duration of running needed to accelerate extinction of cocaine CPP, (aim 2) determine the extent to which new neurons generated from running contribute to accelerated extinction of cocaine CPP, and (aim 3) identify neuropeptides differentially induced in runner versus sedentary animals in the amygdala and hippocampus after exposure to a drug-associated context. The central hypothesis is that new neurons are required for running to accelerate extinction of CPP and that running will alter expression of specific neuropeptides in association with CPP behavior. The rationale is that understanding how running disrupts drug conditioning could be useful for novel treatments for drug addiction. In the first aim, a CPP approach, which has been established as feasible in the applicant's hands, will be used to establish drug-to-context associations in mice. By manipulating the duration for which animals can run, the applicant will determine key temporal parameters that influence the effect of wheel running on CPP. Next, the applicant will directly test the role of ne neurons in the accelerated extinction of CPP from running using an innovative transgenic mouse model in which neurogenesis is selectively reduced. In the third aim, the applicant will use unbiased mass spectrometry technology to quantify neuropeptide profiles in brain region samples. The techniques are already successfully employed in the applicant's laboratory. The proposed research is significant because it will advance our understanding of the mechanisms underlying the beneficial effects of running in facilitating extinction of drug-to-context associations. The proposed research is innovative because it 1) explores the potential of running as a tool to generate brain plasticity and interrupt drug conditioning; 2) directly tests te role of new neurons in accelerated extinction of CPP from running using an innovative transgenic mouse model, and 3) uses state-of-the-art peptidomics technology to identify known and novel neuropeptides that interact with running and cocaine reward. Ultimately, such knowledge has the potential to inform the development of effective therapies for drug addiction and will help to reduce the growing problem of drug addiction in the United States.